SCRIB

{{Short description|Protein-coding gene in the species Homo sapiens}} {{Infobox_gene}} {{For|the early portable computer|Scrib}} '''SCRIB''', also known as '''Scribble''', '''SCRIBL''', or '''Scribbled homolog (Drosophila)''', is a scaffold protein which in humans is encoded by the ''SCRIB'' gene.<ref name="entrez">{{cite web | title = Entrez Gene: SCRIB scribbled homolog (Drosophila)| url = https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=23513}}</ref><ref name="pmid8590280">{{cite journal | vauthors = Nagase T, Seki N, Tanaka A, Ishikawa K, Nomura N | title = Prediction of the coding sequences of unidentified human genes. IV. The coding sequences of 40 new genes (KIAA0121-KIAA0160) deduced by analysis of cDNA clones from human cell line KG-1 | journal = DNA Res. | volume = 2 | issue = 4 | pages = 167–74, 199–210 |date=August 1995 | pmid = 8590280 | doi = 10.1093/dnares/2.4.167| doi-access = free }}</ref> It was originally isolated in Drosophila melanogaster in a pathway (also known as the Scribble complex) with DLGAP5 (Discs large) and LLGL1 (Lethal giant larvae) as a tumor suppressor.<ref name="PMID 12766944">{{cite journal | author = Patrick Humbert | author2 = Sarah Russell | author3 = Helena Richardson| title = Dlg, Scribble and Lgl in cell polarity, cell proliferation and cancer | journal = BioEssays | volume = 25 | issue = 6 | pages = 542–53 |date=June 2003| pmid = 12766944 | doi=10.1002/bies.10286}}</ref> In humans, SCRIB is found as a membrane protein and is involved in cell migration, cell polarity, and cell proliferation in epithelial cells.<ref name="PMID 12766944"/><ref name="PMID 17043654">{{cite journal | author =L E Dow | author2 =J S Kauffman | author3 =J Caddy| author4 =A S Peterson | author5 =S M Jane| author6 =S M Russell | author7 =P O Humbert | name-list-style =amp | title = The tumour-suppressor Scribble dictates cell polarity during directed epithelial migration: regulation of Rho GTPase recruitment to the leading edge | journal = Oncogene | volume = 26 | issue = 16 | pages = 2272–82 |date=April 2007 | pmid = 17043654 | doi=10.1038/sj.onc.1210016| doi-access =free }}</ref> There is also strong evidence that SCRIB may play a role in cancer progression because of its strong homology to the Drosophila protein.<ref name="PMID 12766944"/>

== Function ==

In ''Drosophila melanogaster'', SCRIB is involved in synaptic function, neuroblast differentiation, and epithelial polarization. Mechanistically, the human homolog is a scaffold protein linked to cellular differentiation centered on the regulation of epithelial as well as neuronal morphogenesis. Deficiency in SCRIB impairs many aspects of cell polarity and cell movement. SCRIB is also likely involved in establishing apical-basal polarity as well as progression from the G1 phase to S phase in the cell cycle as a result of its relationship with cell proliferation and exocytosis.<ref name="PMID 17043654"/>

The transcribed protein products of the SCRIB gene along with DLGAP5 (Discs large) and LLGL1 (Lethal giant larvae) are components of the Scribble complex that is localized in the basolateral membrane. The Scribble complex plays a role in determining cell polarity and cell proliferation in epithelial cells.<ref name="Royer_Lu_2011">{{cite journal | vauthors = Royer C, Lu X | title = Epithelial cell polarity: a major gatekeeper against cancer? | journal = Cell Death Differ. | volume = 18 | issue = 9 | pages = 1470–7 |date=September 2011 | pmid = 21617693 | pmc = 3178423 | doi = 10.1038/cdd.2011.60 }}</ref> The precise mechanism by which these proteins function together is currently unknown, but they have been implicated in several signaling pathways, vesicle trafficking, and in the myosin II-actin cytoskeleton.<ref name="PMID 12766944"/> The Scribble complex has been shown to promote basolateral membrane identity by antagonizing both the Par complex and the Crumbs complex, which promote apical membrane identity.<ref name="Royer_Lu_2011"/> These genes have also been identified as tumor suppressors in ''Drosophila melanogaster''. Since these genes are highly conserved in humans, there is evidence that they play a role in cancer progression.<ref name="PMID 12766944"/>

== Structure ==

The human homolog is a LAP protein, it contains 16 leucine-rich repeats and four PDZ domains.<ref name="pmid12499390">{{cite journal | author = Jennifer N. Murdoch | author2 = Deborah J. Henderson | author3 = Kit Doudney | author4 = Carles Gaston-Massuet | author5 = Helen M. Phillips | author6 = Caroline Paternotte | author7 = Ruth Arkell | author8 = Philip Stanier | author9 = Andrew J. Copp | name-list-style = amp | title = Disruption of scribble (Scrb1) causes severe neural tube defects in the circletail mouse. | journal = Hum. Mol. Genet. | volume = 12 | issue = 2 | pages = 87–98 |date=November 2002 | pmid = 12499390 | doi=10.1093/hmg/12.2.87| doi-access = free }}</ref> SCRIB belongs to a protein complex containing betaPIX, an exchange factor for Rac/Cdc42, and GIT1, a GTPase activating protein for ARF6 implicated in receptor recycling and exocytosis.<ref name="pmid18716323">{{cite journal | vauthors = Nola S, Sebbagh M, Marchetto S, Osmani N, Nourry C, Audebert S, Navarro C, Rachel R, Montcouquiol M, Sans N, Etienne-Manneville S, Borg JP, Santoni MJ | title = Scrib regulates PAK activity during the cell migration process | journal = Hum. Mol. Genet. | volume = 17 | issue = 22 | pages = 3552–65 |date=November 2008 | pmid = 18716323 | doi = 10.1093/hmg/ddn248 | doi-access = free }}</ref>

== Subcellular and tissue distribution ==

SCRIB is found in the cell membrane most often as a peripheral membrane protein. The Scribble complex is localized at the basolateral membrane.<ref name="Royer_Lu_2011"/> SCRIB is also found in cellular junctions such as adherens junctions and tight junctions.<ref name="PMID 15649318">{{cite journal | vauthors = Petit MM, Meulemans SM, Alen P, Ayoubi TA, Jansen E, Van de Ven WJ | title = The tumor suppressor Scrib interacts with the zyxin-related protein LPP, which shuttles between cell adhesion sites and the nucleus. | journal = BMC Cell Biol. | volume = 6 | issue = 1 | pages = 1 |date=January 2005 | pmid = 15649318 | doi=10.1186/1471-2121-6-1 | pmc=546208 | doi-access = free }}</ref> Specifically, it is located in the kidney, skeletal muscles, liver, lung, breast, intestine, placenta and epithelial cells.<ref name="PMID 15806148">{{cite journal | vauthors = Navarro C, Nola S, Audebert S, Santoni MJ, Arsanto JP, Ginestier C, Marchetto S, Jacquemier J, Isnardon D, Le Bivic A, Birnbaum D, Borg JP | title = Junctional recruitment of mammalian Scribble relies on E-cadherin engagement | journal = Oncogene | volume = 24 | issue = 27 | pages = 4330–9 |date=June 2005 | pmid = 15806148 | doi=10.1038/sj.onc.1208632| doi-access = free }}</ref>

== Clinical significance ==

The PDZ domain of SCRIB binds directly to the human papillomavirus E6 protein.<ref name="pmid11027293">{{cite journal | vauthors = Nakagawa S, Huibregtse JM | title = Human scribble (Vartul) is targeted for ubiquitin-mediated degradation by the high-risk papillomavirus E6 proteins and the E6AP ubiquitin-protein ligase | journal = Mol. Cell. Biol. | volume = 20 | issue = 21 | pages = 8244–53 |date=November 2000 | pmid = 11027293 | pmc = 86433 | doi = 10.1128/MCB.20.21.8244-8253.2000}}</ref> SCRIB is targeted for ubiquitination by a complex of E6 and UBE3A and E6 induces degradation of SCRIB.<ref name="pmid11027293"/>

=== Role as a tumor suppressor ===

As mentioned above, SCRIB has been identified as a tumor suppressor along with DLGAP5 (Discs large) and LLGL1 (Lethal giant larvae).<ref name="PMID 12766944"/> Specifically, SCRIB deficient mutants have been shown to promote the activity of numerous oncogenes.<ref name="Royer_Lu_2011"/> For example, SCRIB is known to inhibit breast cancer formation and the depletion of SCRIB promotes neoplastic growth by disrupting morphogenesis and inhibiting cell death through an association with Myc.<ref name="Royer_Lu_2011"/><ref name="pmid19041750">{{cite journal | vauthors = Zhan L, Rosenberg A, Bergami KC, Yu M, Xuan Z, Jaffe AB, Allred C, Muthuswamy SK | title = Deregulation of scribble promotes mammary tumorigenesis and reveals a role for cell polarity in carcinoma | journal = Cell | volume = 135 | issue = 5 | pages = 865–78 |date=November 2008 | pmid = 19041750 | doi = 10.1016/j.cell.2008.09.045 | pmc=3015046}}</ref> In human cells expressing oncogenic Ras or Raf, it was found the loss of SCRIB resulted in the invasion of the extracellular matrix by various cell types. This is believed to be a direct result of regulation of the MAP Kinase pathway by SCRIB.<ref name="PMID 18641685 ">{{cite journal | author = L E Dow | author2 = I A Elsum | author3 = C L King| author4 = K M Kinross | author5 = H E Richardson | author6 = P O Humbert | name-list-style = amp| title = Loss of human Scribble cooperates with H-Ras to promote cell invasion through deregulation of MAPK signalling | journal = Oncogene | volume = 27 | issue = 46 | pages = 5988–6001 |date=July 2008 | pmid = 18641685 | doi=10.1038/onc.2008.219| doi-access = free }}</ref>

=== Role in epithelial mesenchymal transition (EMT) ===

Due to its role in cell polarity and cell motility, SCRIB has also been implicated in epithelial mesenchymal transition (EMT), which is linked to tumor metastasis and proliferation in many cancers. EMT is implicated in cancer progression by allowing static epithelial cells to become migratory and allowing these cells to adapt to as well as colonize new environments. In cancerous epithelial tissues, SCRIB is found primarily in the cytosol as opposed to its usual location in the membrane, thus further implicating a role in tumor progression and EMT for SCRIB.<ref name="PMID 21549346">{{cite journal | author = Valentina Vaira | author2 = Alice Faversani | author3 = Takehiko Dohi | author4 = Marco Maggioni | author5 = Mario Nosotti | author6 = Delfina Tosi | author7 = Dario C Altieri | author8 = Silvano Bosari| title = Aberrant Overexpression of the Cell Polarity Module Scribble in Human Cancer | journal = The American Journal of Pathology | volume = 178 | issue = 6 | pages = 2478–83 |date=June 2011| pmid = 21549346 | doi=10.1016/j.ajpath.2011.02.028 | pmc=3124121}}</ref>

Knockdown mutants have resulted in the loss of adhesion between Madin-Darby canine kidney epithelial cells. This loss of adhesion was correlated with an acquired mesenchymal appearance, an increase in motility, and loss of directionality. These effects were a direct result of the interruption of E-cadherin-mediated cellular adhesion.<ref name="pmid16344308">{{cite journal | author = Yi Qin | author2 = Christopher Capaldo | author3 = Barry M. Gumbiner | author4 = Ian G. Macara | name-list-style = amp | title = The mammalian SCRIB polarity protein regulates epithelial cell adhesion and migration through E-cadherin | journal = Journal of Cell Biology | volume = 171 | issue = 6 | pages = 1061–71 |date=December 2005 | pmid = 16344308 | doi=10.1083/jcb.200506094 | pmc=2171311}}</ref> A decrease in cell migration and an overall decrease in cell motility markers as well as epithelial mesenchymal transition mediators was also observed in small lung adenocarcinoma cells that were depleted of SCRIB.<ref name="PMID 21549346"/>

== References == {{reflist|35em}}

== Further reading == {{refbegin|35em}} *{{cite journal |vauthors=Nakajima D, Okazaki N, Yamakawa H, etal |title=Construction of expression-ready cDNA clones for KIAA genes: manual curation of 330 KIAA cDNA clones. |journal=DNA Res. |volume=9 |issue= 3 |pages= 99–106 |year= 2003 |pmid= 12168954 |doi=10.1093/dnares/9.3.99 |doi-access=free }} *{{cite journal |vauthors=Nagase T, Seki N, Tanaka A, etal |title=Prediction of the coding sequences of unidentified human genes. IV. The coding sequences of 40 new genes (KIAA0121-KIAA0160) deduced by analysis of cDNA clones from human cell line KG-1. |journal=DNA Res. |volume=2 |issue= 4 |pages= 167–74, 199–210 |year= 1996 |pmid= 8590280 |doi=10.1093/dnares/2.4.167 |doi-access=free }} *{{cite journal | vauthors=Nakagawa S, Huibregtse JM |title=Human scribble (Vartul) is targeted for ubiquitin-mediated degradation by the high-risk papillomavirus E6 proteins and the E6AP ubiquitin-protein ligase. |journal=Mol. Cell. Biol. |volume=20 |issue= 21 |pages= 8244–53 |year= 2000 |pmid= 11027293 |doi=10.1128/MCB.20.21.8244-8253.2000 | pmc=86433 }} *{{cite journal |vauthors=Strausberg RL, Feingold EA, Grouse LH, etal |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899–903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 | pmc=139241 |bibcode=2002PNAS...9916899M |doi-access=free }} *{{cite journal |vauthors=Dow LE, Brumby AM, Muratore R, etal |title=hScrib is a functional homologue of the Drosophila tumour suppressor Scribble. |journal=Oncogene |volume=22 |issue= 58 |pages= 9225–30 |year= 2004 |pmid= 14681682 |doi= 10.1038/sj.onc.1207154 |doi-access= free }} *{{cite journal |vauthors=Nakagawa S, Yano T, Nakagawa K, etal |title=Analysis of the expression and localisation of a LAP protein, human scribble, in the normal and neoplastic epithelium of uterine cervix. |journal=Br. J. Cancer |volume=90 |issue= 1 |pages= 194–9 |year= 2004 |pmid= 14710229 |doi= 10.1038/sj.bjc.6601465 | pmc=2395302 }} *{{cite journal |vauthors=Bouwmeester T, Bauch A, Ruffner H, etal |title=A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway. |journal=Nat. Cell Biol. |volume=6 |issue= 2 |pages= 97–105 |year= 2004 |pmid= 14743216 |doi= 10.1038/ncb1086 |s2cid=11683986 }} *{{cite journal |vauthors=Brill LM, Salomon AR, Ficarro SB, etal |title=Robust phosphoproteomic profiling of tyrosine phosphorylation sites from human T cells using immobilized metal affinity chromatography and tandem mass spectrometry. |journal=Anal. Chem. |volume=76 |issue= 10 |pages= 2763–72 |year= 2004 |pmid= 15144186 |doi= 10.1021/ac035352d }} *{{cite journal | vauthors=Lehner B, Sanderson CM |title=A protein interaction framework for human mRNA degradation. |journal=Genome Res. |volume=14 |issue= 7 |pages= 1315–23 |year= 2004 |pmid= 15231747 |doi= 10.1101/gr.2122004 | pmc=442147 }} *{{cite journal | author=Borg JP |title=[hScrib: a potential novel tumor suppressor] |journal=Pathol. Biol. |volume=52 |issue= 6 |pages= 328–31 |year= 2004 |pmid= 15261375 |doi= 10.1016/j.patbio.2003.09.015 }} *{{cite journal |vauthors=Beausoleil SA, Jedrychowski M, Schwartz D, etal |title=Large-scale characterization of HeLa cell nuclear phosphoproteins. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=101 |issue= 33 |pages= 12130–5 |year= 2004 |pmid= 15302935 |doi= 10.1073/pnas.0404720101 | pmc=514446 |bibcode=2004PNAS..10112130B |doi-access=free }} *{{cite journal |vauthors=Ballif BA, Villén J, Beausoleil SA, etal |title=Phosphoproteomic analysis of the developing mouse brain. |journal=Mol. Cell. Proteomics |volume=3 |issue= 11 |pages= 1093–101 |year= 2005 |pmid= 15345747 |doi= 10.1074/mcp.M400085-MCP200 |doi-access= free }} *{{cite journal |vauthors=Gerhard DS, Wagner L, Feingold EA, etal |title=The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). |journal=Genome Res. |volume=14 |issue= 10B |pages= 2121–7 |year= 2004 |pmid= 15489334 |doi= 10.1101/gr.2596504 | pmc=528928 }} *{{cite journal |vauthors=Petit MM, Meulemans SM, Alen P, etal |title=The tumor suppressor Scrib interacts with the zyxin-related protein LPP, which shuttles between cell adhesion sites and the nucleus. |journal=BMC Cell Biol. |volume=6 |issue= 1 |pages= 1 |year= 2006 |pmid= 15649318 |doi= 10.1186/1471-2121-6-1 | pmc=546208 |doi-access=free }} *{{cite journal |vauthors=Barrios-Rodiles M, Brown KR, Ozdamar B, etal |title=High-throughput mapping of a dynamic signaling network in mammalian cells. |journal=Science |volume=307 |issue= 5715 |pages= 1621–5 |year= 2005 |pmid= 15761153 |doi= 10.1126/science.1105776 |bibcode=2005Sci...307.1621B |s2cid=39457788 }} *{{cite journal |vauthors=Lahuna O, Quellari M, Achard C, etal |title=Thyrotropin receptor trafficking relies on the hScrib-betaPIX-GIT1-ARF6 pathway. |journal=EMBO J. |volume=24 |issue= 7 |pages= 1364–74 |year= 2005 |pmid= 15775968 |doi= 10.1038/sj.emboj.7600616 | pmc=1142541 }} *{{cite journal |vauthors=Navarro C, Nola S, Audebert S, etal |title=Junctional recruitment of mammalian Scribble relies on E-cadherin engagement. |journal=Oncogene |volume=24 |issue= 27 |pages= 4330–9 |year= 2005 |pmid= 15806148 |doi= 10.1038/sj.onc.1208632 |doi-access= free }} *{{cite journal |vauthors=Métais JY, Navarro C, Santoni MJ, etal |title=hScrib interacts with ZO-2 at the cell-cell junctions of epithelial cells. |journal=FEBS Lett. |volume=579 |issue= 17 |pages= 3725–30 |year= 2005 |pmid= 15975580 |doi= 10.1016/j.febslet.2005.05.062 |s2cid=4893407 |doi-access=free }} *{{cite journal |vauthors=Thomas M, Massimi P, Navarro C, etal |title=The hScrib/Dlg apico-basal control complex is differentially targeted by HPV-16 and HPV-18 E6 proteins. |journal=Oncogene |volume=24 |issue= 41 |pages= 6222–30 |year= 2005 |pmid= 16103886 |doi= 10.1038/sj.onc.1208757 |doi-access= free }} {{refend}}